delta17, 20-pregnenolal derivatives



Patented Dec. 4, 1951 2,577,018 AWRQ-PPREGNENOLAL DERIVATIVES Edward C.Kendall and Gerard A. Fleisher, Rochester, Minn, assignors to ResearchCorporation, New York, N. Y., a. corporation of New York NoDrawing.Application November 20, 1950, Serial No. 196,701

Claims. 1

m This invention relates to steroids useful in the synthesis of adrenalcortical hormones and particularly to steroids having a glyoxal sidechain at 0-17 of the steroid ring system and to the ketol derivativesthereof.

The new compounds of the invention include zglyoxals of the generalformula :(A)

2 wherein Hal and Ac are as defined above, R1 is a member-of the groupconsisting of --CH0 and -CH(OAC)z, and Y is a member of the groupconsisting of hydrogen and organic carboxylic acid radicals.

The novel methods of the invention include the reaction of bromine witha 3(a) ,21-diacyloxy- 11,20-diketo-12 (a) halopregnane in approximatelyequimolecular proportions to produce a 3(a),21- diacyloxy11,20-diketo12(a) ,2l-.dihalopregnane, and the reaction of a3(a),21-diacyloxy-11,20- diketo-12'(-a,) -halopregnane with a largeexcess of bromine to form the corresponding 17-haloglyoxals.

The invention also comprises the method of converting compounds ofFormula A wherein X is hydrogen into compounds of Formula B by treatmentwith an organic nitrogen base such as pyridine, collidine and-quinoline,and the method of converting compounds of Formula A wherein R is -CH0and X is bromine into compounds of v Forn1ula B by treatment with analkali metal bisulfite.

The compounds and methods of the invention are illustrated by thefollowing flow sheet. In the compounds illustrated in the flow sheet theacyl group Ac may be any organic earboxylic acid, the lower fatty acidssuch as acetic and propionic acids being particularly suitable, andbromine maybe replaced by chlorine.

B I I x fij W03 AcO When 3(a) ,21-diacetoxy 11,20 diketo-l2(a)bromopregnane (I) is brominated with one mole of bromine in drychloroform at 0 with gaseous I-lBr as the catalyst, the reaction iscomplete in 4 hours and practically all of the material can be separatedin crystalline form. Recrystallization from chloroform-ligroin revealsthe presence of two isomeric compounds. The less soluble one, herereferred to as bromide a (compound III), is present in somewhat largeramounts. It crystallizes in flat plates, M. P. HBO-182, with a strongdecomposition. (a)D|-l39 (0:1 in chloroform) +133 (0:1 in HOAc). A max.312.5 m ,Z:276 (chloroform). Analysis shows that one additional bromineatom has entered the molecule.

The more soluble compound, bromide b (compound IV), crystallizes inprismatic needles. The pure crystals melt at 147-48, resolidify, andmelt again at 167-173" with strong decomposition.- (a)D94-. (0:1 inchloroform); 73 (0:1 in HOAc). A max. 313.5 m ,E:304 (chloroform).Analysis shows bromide b to be isomeric with bromide a.

In the process of separation the rotation of the mother liquorscontaining bromide 1) changes in a positive direction on standing andmore bromide a can then be separated. Also, if impure bromide a is keptin solution longer than usual its. rotation decreases. It is not knownwhat impurity catalyzes this mutarotation, but it can be demonstratedthat I-lBr has such an effeet. A change in specific rotation of bothpure compounds occurs in glacial acetic acid N/ with HBr at 33 C.Equilibrium is reached when about 60 per cent of bromide a and per centof bromide b are present.

In order to determine the position of the newly entered bromine in bothcompounds (bromide a can be recovered in practically quantitative yield.

(2) Replacement with the acetoxy group. When either bromide a or bromideb is dissolved in a mixture of benzene and glacial acetic acid andshaken with excess silver acetate for 2 days,

3(a),21,21 triacetoxy 11,20 diketo 12(a) bromo-pregnane (VII) isobtained in 88 and 89% yield, M. P. 169.5-1'70.5; (a) +35 (c-1 inCHCls), A max. 310 m 2:190 (MeOI-I). This substance reduces bothammoniacal silver nitrate and phosphomolybdic acid but less intenselythan the ketol acetate (I) With sodium acetate in acetic acid the samecompound (VII) is obtained from I but in smaller yields. The triacetateis completely de- 7 brominated with zinc and acetic acid to 3 (a) ,21,21triacetoxy-11,20-diketopregnane (XII) which crystallizes from a littleMeOI-I in short rods, M. P. 11 516. (a) |117 (c=1 in CHC13).

When 3(a),2l,21 -'triacetoxy 11,20 diketo- 12(a)-brgmopregnane (VII) isheated in methseason anolic HC l andsubseguentiy=-reacetsna-tedat =3 3(aacetoXy- '2'L2-1 dimethoxy irs-marks; to-12(a)bromopregnane (X1) isobtained'in 80%- yield. It crystallizes in long; fine needles; M. P. 158160". (a)' +30 (O I in CI-ICla).

Hydrolysis: Both brom-o compounds (bromide a and bromide 17) react Withaqueous pyridine almost as fast as they go into solution. When such asolution or either brorno compoiind. is poured intoexcess sulfuric acidand filtered, one equivalent of bromide-ion is foundj in the filtrate.The precipitate can be crystallized quantitatively from aqueous acetoneor" aqueous acetic acid (needles). It has the properties of a hydratedglyoxal, in that it formsyel'low solutions in am hydrous solvents suchas benzene; glacial acetic acid, chloroform; etc., but colorlesssolutions' iii alcohols or aqueous solvents. The yellow color is due tothe free glyoXaIII which eiz'hibits' a small band at 440 maz -:30, whereinethyl glyoxal absorbs also. The compound reduces ain= inoniac'alsilver nitrate and liberates iodine from HOAc-NaI, though at a slowerrate than the brom'o compounds. The melting point of't'lie'hydi'ate isnot sharp and depends on the rate of heating, as it loses water to givethe g'lyoxal. When p1ace'd on the Stage at 147 it melts at Pi -51. (a)+28.0 (c 1 if). CHCls). the yeuow color appears in the chlbfoforfhsOlliti'dfi the rotation drops to (a) +2 6 (calculated as glyoxal). Thecompound is, therefore, fbr'rfiil-= latd 33S 3(a)a.ctoX$-2I,21-dihydf6}iy11,20- diketo-12(c) -bromopregriafi (VI).

The free glyoxal' IIhas Ildt been Obtained iii crystallihe form. W

When the g'lyoxal' hydrate VI is treated with methanolic I-ICI, renewedby' r'actyl'ation, the dimethyl acet'al (XI) is obtained which isidentical with the product prepared from the triacetate VII. when theg1'y'cxa1 hydrate VI is treated with aceticanhydriae and a drop ofconcentrated H2804 the sametiiacetate VII is obtaind, while treatmentwith acetyl bromideand H2804 yields a mixture of brcmoacetates fromwhich pure bromide d (Iincomd be. isolated ((a) 137, Ml Pl 180-82). Thetotal remote or the reaction product suggested the. presence of over 40%ofb'romid'e 6 (compound IV), but in the attempted isolation it partiallyisomenzed to bromide a (compound III). That ho other reactions occurwith acetyl' bromide is indicated by the observaticn thatre'dilction ofthe whole prodnet with sodium iodide in acetic acid gives an excellentyield of 3(a) ,21-diacetoxy-1l,20-diketo- 12(a) -bromopregnan (I).

i It is believed that the foregoing reactions show -that both brornocompounds III and. IV are. the C'i'rdiastercoisorners. This is alsosupported by a comparison of the Optical rotations of related compounds.7 k M When a pyridifre solution of the gfydiial II or ryoxai hydrate VI:is heated on the steam bath for one hour and the solvent then replacedwith chloroform, an absorption band at 284' inn is observed. It wassubsequently found that more or the light absorbing material can beobtained by using a mixture of one part py'ri'dih'e and rear partsglacial acetic acid and heating at 60"for '16 hours. Further heatingcauses a gradual loss of the absorption after an optimum of about27:6,2'60. The reaction also takes place at room temperature, butrequires several days. Water is found to inhibit the reaction somewhat.Ades orp'ticn of the mixture'on magnesium "silicate infusorial earth andelution with benzene leaves 6 the non-absorbing material on the columnvand gives acrystalline product of M; P.- l-82 after removal of thebenzene. several recrystallizations from dilute acetone gives a productof M. P. l- 9l (a) -+9 6 cc=0.as in chloroform), x max.=2 84 my;E=-1=3,650 (chloroform) A max. 282 m 2'=12,500 (MeOH).

This product reduces ammoniacal silver sol'u tion and showed a greenishbrown color when a drop of alcohol Fe'Cls solution is added to itssolution in alcohol. With tetraiiitroniethar'ie it gives a weaklypositive reaction. Iii chloroform solution it reacts with 1 mole ofbromine with-iii 15 minutes. These tests, the absorption curve and theanaylsis showthat this compound is the enol derivativeof the glyoxal; i.a. 3M) acetoxy 20 hydroxy' 11 keto 12(a) --bromo- A 'pregnene-21-al (X).

On acetylation with pyridine acetic anhydride the enol is converted toits acetyl derivative (XIII) of M. P. 162-64 (leaflets from diluteacetone). (a) '['86 (c'-1 in chloroform), A max. :246 m 2'=l2,500(ether). In methanol the absorption decreases continuously which may bedue to acetal formation. The substance does not give the FeClz-ieactionfor free enol; it reduces ammoniacal silver nitrate and takes upbromine, though ata much slower rate than the free enol.

The shift of the absorption. maximum 011 acetylation from 284 my to 246m is again in keeping with the observations on the enol derivatives ofa-diketones where in each case the enol acetate shows the normalabsorption of an asubstituted Jr-unsaturated ketone.

The enol acetate (XIII) can be formed directly from either21-bromocompound (III or IV) when treated with a mixture of equal parts ofpyridine and glacial acetic acid, etg'. at room temperature for 2 days.Absorption analysis reveals that under such conditions there is formedover 30% of enol acetatev together with a nearly equal amount of freeenol while the remaining third does not obsorb light and is perhapspolymerized glyoxal. When the glyoxal (II) is subjected to the sameconditions, a similar amount of enol is formed, while the absorptionband of the. enol acetate is completely absent. This suggests that theenol is formed by way of the glyoxal, but that a different mechanism isinvolved the formation of the; enol acetate.

When the enol acetate XIII is treated with acetic anhydride and a dropof concentrated H2804, a good yield of 3,20,21,21-tetraacetoxy-l1keto-12(a)-bromo-A -pregnene (XIV) is obtained. After recrystallization,M. P. 15455 (needles), (a) +60 (c-l in CHC13). The crystals do not givethe enol reaction with FeCls. They absorb 1 mole of bromine within 3hours.

When 3(a),21 diacetoxy-11,20-diketo-12(a)- bromo-pregnene (I) is treatedwith a large excess of bromine and I-IBr in glacial acetic acid for 30hours at 30, a crystalline dibromo compound separates from the benzeneextract in about 30% yield which has all the characteristics of ahydrated glyoxal. It forms yellow solutions in anhydrous solvents, butcolorless solutions in methanol or aqueous solvents. The 17-bromoglyoxal V has not been separated in crystalline form but like theglyoxal II may be recovered as its hydrate IX. The yellow color is dueto a small band at 423 m E-40. The melting point depends on the rate ofheating. When the crystals are put on the hot stage at 203 they turnyellow immediately and melt with strong decomposition at 206-08". (M-345 (c-1 in chloroform); the solution soon turns yellow and therotation changes to (a) 37 (calcd. as glyoxal). The compound analyzes as3(a)- acetoxy 21,21 dihydroxy 11,20 diketo 12 (a),l7-dibromopregnane(IX). When the crystals of IX are treated with acetic anhydride H2804 acrystalline derivative is obtained, M. P 167-69", (M -24 (c-l inchloroform). This is the 3(a),21,21-triacetoxy-l1,20-diketo-12(a),-l7-dibromopregnane (VIII).

When the 17 bromoglyoxal hydrate (IX) is heated in dilute methanol inthe presence of excess NaHSOa, crystals appear after a few minutes whichexhibit an absorption maximum at 284 mu. After recrystallization fromdilute acetone, M. P. 189.5-90", (a) +101 (c-1 in chloroform xmax.=284 m2=10,900 (methanol) it analyzes as 3(a) ,20 dihydroxy 11 keto 12(a)-bromon -pregnene-m-al (XV), and must be formed, therefore, by reductiveremoval of the bromine atom at -17 together with hydrolysis at C-3.

Compound XVI may be produced from compound VI by treatment with acetylchloride and compound XVI may be reconverted into compound VI bytreatment with pyridine.

Details of the procedures outlined above are given in the followingspecific examples:

Preparation of starting material, 3,21-diacetcry-11,20-diketo-1Z-bromopregnane (I) 3 (a) 21-diacetoxy-l1-keto- 12-bromo-24,24-diphenyl- A choladiene is dissolved in ethyl acetate andtreated with ozone at a temperature of -78 until approximately 2 molesof ozone have been absorbed. By this treatment the diene is broken atthe bond 20,22 and the compound 3(a),21dl acetoxy-11,20-diketo-l2 (a)-bromopregnane crystallizes from solution. Recrystallization of thematerial from chloroform-methanol raises the melting point to 164-165".(All rotations were taken in chloroform (c-1) 21-bromide a (III) andZI-bromide I) (IV) from 3 (a) ,21-diacetoa:y-11,20-diiceto-12(a)-bromopreg-- nane (I) .20.46 gm. 3(a),21-diacetoxy-11,20-dlketo-12(a)-bromopregnane mm.) dissolved in 400 cc. chloroform arecooled in an ice bath. To this is added 80 cc. of 1 N Bra in CHCla. Withcooling, gaseous HBr is now passed into the flask for 10 minutes. Thesolution is allowed to stand in an ice bath for three hours. .Thestraw-colored solution is concentrated underreduced pressure to a smallvolume, fresh chloroform added and again concentrated under reducedpressure. On adding much ligroin the material crystallizes in aboutyield and shows a specific rotation, (at) =+34". When dissolved in 40cc. chloroform and 200 cc. of ligroin added about one-half of thematerial crystallizes, with (a) =l-106. After five recrystallizations inthe same manner the rotation is constant at (a) =+139. This compound,bromide a, crystallizes in flat plates, M. P. ISO-182 with strongdecomposition.

From the mother liquor of the first recrystallization the other half Ofthe reaction product is obtained by removing most of the chloroformunder reduced pressure and adding a large amount of ligroin. A specificrotation (a) =38 is found for this fraction. When it is recrystallizedfrom a little chloroform and much ligroin its rotation finally reaches((1) -94", after seven to nine recrystallizations. This compound,bromide b, crystallizes in prismatic needles, M. P. 147-48" withresolidification, then 167-73 with strong decomposition.

3(a),21,21 triacetoxy 11,20 dilceto 12a)- bromopregnane (VII) frombromide 11. (III) and bromide b (IV) with. silver acetate.590 mg. ofeither pure bromide a or pure bromide b is dissolved in 5 cc. benzene.15 cc. glacial acetic acid and 334 mg. silver acetate are added and themixture is agitated at room temperature for 45 hours. It is thenfiltered and washed with chloroform. The combined filtrates are washedwith water, sodium bicarbonate solution and again with water and dried.The material which remains after removal of the chloroform isrecrystallized from methanol, yielding from both bromide a and bromide b88-89 per cent of pure 3(a),21,21 diacetoxy 11,20 diketo-12(a)bromopregnane, M. P. 1695-1705",

, (a) +35. This compound reduces both ammoniacal silver nitrate andphosphomolybdic acid, but less intensely than the ketol acetate (I)3(a),21,21 triacetoxy 11,20 dilceto 12(a) bromopregnane (VII) frombromide a (III) and bromide b (IV) with. sodium acetate.590 mg. ofeither pure bromide a or bromide b is mixed with 5 cc. of a M/3 sodiumacetate solution in acetic acid and heated on the steam bath for 2hours. Water is then added and the precipitate dissolved in chloroform.The latter is washed with water, sodium bicarbonate and water and dried.After removal of the chloroform under reduced pressure the residue isrecrystallized several times from methanol until the melting pointreaches 1695-1705". This material gives no depression of its meltingpoint when mixed with 3(a) ,21,21- triacetoxy 11,20 diketo 12(a)-bromopregnane obtained by the silver acetate method. The yield of purematerial is only about 60 per cent in spite of the quantitative removalof the bromine as judged by titration of the water washings.

3(a),21,21 triacetoxy 11,20 diketopregmme (XII) from3(a),21,21-triacet0my11,20-diketo- 12(v.)-bromopregnane (VII) .3.0 g.triacetate VII is dissolved in 60 cc. glacial acetic acid. This iscooled with cold water and 3.0 g. zinc dust added. It is then allowed tostand at room temperature for 1 hour, filtered and the residue washedthoroughly with chloroform and water. The chloroform extract is washedwith water, sodium bicarbonate and water, dried with sodium sulfate andevaporated. The residue crystallizes from a little methanol afterseeding. Weight 2.445 gm. (95%) M. P. -16 (short rods). s-sew?- 3,acetorcy 21,21 dtmethory; 1,1,20 diket-12(a)-bromopreg,n ne (X!) from3( ),-21,21- triacetory 11,20 dikejto .-1 2(,a),-h1-omopregncne (VI I).,,-5.69,5 gm. of 321,21etriacetoxy 11,20-di keto-lZ (Mbrcmopregnane and160 .cc. of N/4 H01 in MeQl-I is refluxed for 2 hours. Aftercooling thesolution is mixed with .gm. K2003 in cc. Water and. then concentrated invacuum. Some more water is added and it is ,concentrated further. It isextracted with chloroform, ,washed two times with water, driedandevaporated. To re-establish the acetoxy group at C53 the residue isdissolved in 20 cc. pyridine and 20 cc. acetic anhydride added. It isallowed tostand at .rgom temperature overnight. The next morning ice isadded. After .20 minutes it is filtered and washed thoroughly .withwater. The n aterial I crystallizes from dilute methanol in long, fineneedles, weight 4,115 .gm. .(80 per centLlM. IP. 153- 58. After .tworecrystallizations from dilute MeOI-I, the M. P. is constant at 157 599..I.

3(a) acetozry 21,21- cZihydr9$y 1 1,2!) dike,- t0-1 2(a) abromopregna e(VI) from ,b1tomide a (III) or bromide b (I V),.236 mg. (0.4 min.) .ofeither pure bromide a or pure hromideh is dissolved in 2 cc. of 80 per'cent .pyridine at .room temperature. Aft.er..15 min tesirom thetimeofmixing the colorless solution is poured into '2 cc. of 10 N H2SO4 and.ice. It is filtered off and washed thoroughly with water thendried. The

dry reaction product is dissolved in acetic ,acid and water is addedcarefully. 142 mghf small needles a e t ed a th fi st a d 1 -1 ea thesecond fcrop, a yield off39per cent. Flor an ly e r t r p Iisp c morerecr s al a from dilute acetic .acid, ,P. 129-140 with ,de} composition.When plfitce d on the stage at 147 it melts at 1 -51 w th decom osition(a) =+2 8. As the yellow color appears inthe chloroform (a) b+26(calculated as glyoxal) 3(a) acelosc y 21,21 -dimethoguy [11,20 di-7ceto-1-2(a)-bromopregn ne (X 1) from acetoosy 21,21- dihydromy -11, 2 0dz'lqeto 1;2( a bromopregnane (V1),- 100 mg. of crystallinehydrate ofthe glyoxal (VI) is dissolved :warm benzene, the solvent taken down todryness in vacuum, the residue again dissolved in boiling benzene andconcentrated in vacuum. This process is repeated once more. Thebenzenefree residue is now refluxed with 4 cc. MeCH, 0.25 normal withdry :HOl lfor 2 hours. It is cooled and an excess NagCOs solution andiceare added. It is extracted with chloroform, and the ,40 sohltion' the.ro ii n r s is extract iswashed until neutral,.dri,ed,over sodiumsulfate and evaporated. The residue isdissolved in 1 cc. dry pyridineand 1 cc aceticanhydride added. After 2.5 hours atroom temperature, iceis added. After abouta half hour it is extracted with chloroform, theextract washed once ith dilute HCl, then with Nfal-ICO; and withlwater,dried and evaporated. The residue isdissolved in m t no nd W e is add ibturbidi y.

This is f ltered through infusorial earth. More j water is added to thefiltrate, (causing the ,acetal to crystallize, weight 41 mg, M. P. 152531 After one recrystallization from dilute ac'etone crystals r n e fo mof hai lik ne dle weight 32 mg M.P. 1 5 715 9. Thecrystals show nomelting point depression with the ,cornpound prepared from thetriacetate.

3(a),21,21 tr'igzceiory; 11,20 iQZ ZCQIfQ 112$):- bromorrewwne Wm mm 1.a -4i9@ om-i2 .21.- dihydroxy 11,20 -;d i lce,t0 142( bifom opregdrate(V1) is dissolved .with warming in 2 cc.

acetic anhydride. The yellow solution is then cooled with ice and 1 dropconcentrated H2504 added. The color disappears within 2 seconds. After ahalf minute ice is added. It kept at room temperature until the aceticanhydride is all decomposed, then it ,is filteredand thoroughly washedwith water. Weight of the dried material, 114 mg. (theoretical 117 mg),M. P. 156-64. lhe crude material is recrystallized twice from a littlemethanol, yield mg. (77 per cent), M. P. 167-68". The crystals give nomelting point depression with the triacetate obtained from the 2l-bromocompounds.

3 (a') qceto,ry 20 hydrory -11 Iceto 1 2(01)- bromo-A -pregnene-21-aZ(X) from 3( )-acetcry 21,=21-dihydromy 11,20 dikcto I2(0.)-bromopregnane (VI) .1.30 gm. of crystalline 3(a) acetoxy 21,21dihydroxy, 11,20 diketo- 12(11) -bromopregnane (VI) is dissolved in 20cc. of a mixture of 4 parts of glacial acetic acid and 1 part ofpyridine. This is heated at.60 for 16 hours. It is then poured intoexcess mineral acid and ice. The precipitate is filtered and washedthoroughly with water. The dry material weighs 1.09 gm. It has anabsorption band in the ultraviolet light with a maximum at 284 mp,2:6,200 (chloroform). To separate the light-absorbing compound fromlay-products it .is dissolved in benzene and passed through a columncontaining a mixture of 18 gm. magnesium silicate and 18 gm. infusorialearth. The material which is eluted with the first 500 cc. of benzenecrystallizes on the addition of methanol and has an extinctioncoefiicient 2=1 0,900. After several recrystallizations from diluteacetone the crystals melt at -91 and have 1 max.=284 m Z=13,650(chloroform) and (a) =+96.

The compound reduces ammoniacal silver solution and shows a greenishbrown color when a drop of alcoholic FeCl3 solution is added to itssolution in alcohol. With tetranitromethane it gives a Weakly positivereaction. In chloroform solution it reacts With 1 mole of bromine Within15 minutes.

When the time of the reaction is varied, the following yields areobtained, based on the light ab sorption at 284 m 4 hours, 34% of X -'7hours, 40% of X 16 hours, 45% of X 32 hours, 39% of X An increase in therate of formation of X is noted when the amount of aceticacid isreduced; thus, with a mixture of equal parts of acetic acid andpyridine, the following values are found at 60 4 hours, 40% of X 7hours, 45% of X while in pyridine alone the yields are decreased.

3(a) ,20 diacetorcy 11 lceio 1201) bromo n -pregneneal-al (XIII) from3(a)-aceto:ty- 20 hydroxy 11 keto 12(a)bro,mo A 39 pregnene-ZI-al (X).-234 mg. of X are dissolved in 5 cc. pyridine and 5 cc. aceticanhydride. After 1 hour at room temperature it is taken to dryness underreduced pressure. The residue is dissolved in a little chloroform,ligroin is added and the ,miXture concentrated until it ,began to becometurbid. It crystallizes soon in leaflets, yield 229 mg, M. P. 158-61. Ontwo recrystallizations from dilute actone the melting point is constantat 162-64. (a) =+86. The pure compound shows an absorption band withmaximum at 249 m in methanol, but the absorption decreases continuously.When taken in ether the maximum is at 2 16 m 2=12,500. It reducesammoniacal silver nitrate and takes up bromine though at a much slowerrate than the free enol.

3(a) ,20 diacetomy 11 Iceto 12(a) bromo A -pregnene-21-al (XIII) frombromide 0. (III) or bromide I) (IV) .-59.0 mg. of either pure bromide a.or pure bromide b is dissolved in 1.0 cc. of a mixture of "3 partsacetic acid and 1 part pyridine and allowed to stand at room temperaturefor 45 hours. It is then diluted with benzene, washed with water, diluteI-ICl, water, sodium bicarbonate solution and again with water, anddried over sodium sulfate. After removal of the benzene, the residue isdissolved in ether and the light absorption determined. The two maximaat 245 m and 283 m indicate that 51 per cent of the bromide has beenconverted to the enol acetate XIII while 11 per cent is the free enol X.When the relation of acetic acid to pyridine is varied but the otherconditions, i. e., total volume, time and temperature are kept con- Whenthe time of the reaction is extended to five days, the amount of enolacetate generally decreases, while that of the enol increases.

3(a),20,21,21 tetraacetoxy 11 Jceto 12(04) bromo A pregnene (XIV) from3(a),20 diacetomy 11 keto 12(a) bromo A pregnene-Zi-al (XIII) .206 mg.enol acetate (XIII) is dissolved in 4 cc. acetic anhydride. It is cooledwith ice and 2 drops of concentrated sulfuric acid are added. After ahalf minute ice is added and the mixture allowed to stand at roomtemperature until all acetic anhydride is decomposed and the materialcan be filtered. It is washed with water and dried. The crude productweighs 236 mg. and melts at 93-115". It is crystallized from a littleacetone and petroleum ether. Yield, 172 mg, M. P. 150-52". After threerecrystallizations from dilute'acetone, it melts at 154-55 (longneedles). (a) =+60. The crystals absorb one mole Brz within three hours.

3(a) acetoxy 21,21 dz'hydroxy 11,20 diketo 12(o'.) ,17 dz'bromopregnane(IX) from 3(a),21 diacetoxy 11,20 dzlceto 12(00 bromopregnane (I) .10.22gm. of I mm.) is dissolved in 500 cc. glacial acetic acid which contain12.5 cc. bromine and 0.1 mole of dry hydrogen bromide. After 4 days atroom temperature the solution is concentrated under reduced pressure toabout '75 cc., 50 cc. 80 per cent acetic acid are added and removedunder reduced pressure. The remainder is mixed with 50 to 75 cc. ofbenzene. When Water is added white crystals separate at the interphase.Yield 3.4 gm. Th material is purified by recrystallizing it severaltimes from dilute acetic acid until the melting point is 206-08 withdecomposition when placed on the stage at 203. (a) =-34.5. Thesolu'GiQlfl $09 V 12 turns yellow and the rotation changes to (a) =3(calculated as glyoxal).

3 (a),21,21-triaceto:cy-11,ZO-diketo-I2 ((1)17 dibromopregna-ne (VIII)from. 3(a),acetoxy-21,21- dihydrowy-lLZO-diketo 12((1) ,1'7dibromopregname (IX) .50 mg. of IX is dissolved in 2 cc. aceticanhydride and 1 drop of concentrated sulfuric acid added. After a halfminute the mixture is poured on ice. When all acetic anhydride isdecomposed it is filtered and washed thoroughly with water. After dryingthe material is recrystallized first from a little methanol, M. P.158-163, then twice from dilute acetone when the melting point isconstant at 167-69.

3 (a) ,20-dihydroxy-11-keto-12 (a -bromo-A pregnene-ZI-aNXV) from 3(a)aceto.ry-21,21-dihydroxy 11,20 diketo 1.2 (a) ,17 dibromopregname (IX).l.128 g. of IX (2 millimoles) is dissolved in 20 cc. warm methanol,1.04 gm. (10 millimoles) of solid sodium bisulfite is added first, thenslowly and with warming, 40 cc. water. The initial turbidity disappearsas the solution becomes hot. After 3-4 minutes at the boilingtemperature crystals separate, weight 770 mg., M. P. 179-80 (a) Afterseveral recrystallizations from dilute acetone, M. P. 1895-91 max.=284 m2=10,900 in methanol.

3 (a),21-diacetoa:y 11,20 diketo-Z 2 a.) -bromo .21 (a) -chloropregnane(XVI) from 3(a)-acetory- 21,21 dihydroscy-i1,20-di7ceto-12 (a)-bromopregmme (VI).--33'7 mg. of VI is dissolved in 3 cc. acetylchloride and 3 drops concentrated H2SO4 added. It is allowed to stand atroom temperature for 1 hour, mixed with chloroform and shaken vigorouslywith ice. The chloroform layer is washed with water, sodium bicarbonatesolution and again with water, and dried over sodium sulfate. Thechloroform solution after being concentrated to about 1 per cent shows aspecific rotation (a) =+31. On further concentration and addition ofligroin, 173 mg. of crystals hereinafter referred to as chloride 0!.compound XVI are obtained, M. P. -'78, (a) =+63.' Severalrecrystallizations from dilute acetone raise the melting point to aconstant value of 189-91 and the rotation to (a) =+88. From the motherliquor a crop of crystals is obtained with which on severalrecrystallizations gives pure chloride 5 with M. P. 153-54 and (a) =-35.

3(a) acetoxy 21,21 -dihydroa:y 11,20 diketo 12(a) bromopregnane' (VI)from chloride a (XVI) .29 mg. of pure chloride a is suspended in 0.5 cc.80% pyridine. The crystals are in solution after ten minutes at roomtemperature. Twenty minutes later benzene is added and the mixturewashed with excess sulfuric acid.

The benzene extract is washed with sodium bicarbonate and water and istaken to dryness. The residue is crystallized from dilute acetic acid,yield 23 mg. (89%), M. P. 148-49, with yellow color.

All of the compounds I to XVI shown in theforegoing flow sheet, all ofwhich excepting compound XII contain an a-acetate group at position 3,ketone at position 11 and a-bromine at position 12 are new. As isapparent, other acyloxy groups may be substituted for acetoxy atposition 3 and chlorine may be substituted for the bromine at 12.Likewise, other acyloxy 13 groups may be substituted for acetoxy andchlorine for bromine at positions 17, 20 and 21.

This application is a continuation-in-part of our application Serial No.114,462, filed September 7, 1949, now Patent No. 2,563,247.

wherein Hal stands for a halogen of the group 20 consisting of chlorineand bromine.

2. 3(a) ,20 dihydroxy-ll-keto 12(1) bromo- A -pregnene-21-al.

3. The method which comprises heating a 3(a) acyloxy 21,21dihydroxy-11,2O diketo -12(a) halo-17-bromopregnane with an aqueoussolution of an alkali metal bisulfite to produce a 3(0) ,20- dihydroxy11-keto-12-(-a) halo-A -pregnene 21-al.

4. The method as defined in claim 3 in which the bisulfite is sodiumbisulfite.

5. The method which comprises heating 3(a)- acetoxy 21,21-dihydroxy11,20 diketo-12(a) I'Z-dibromopregnane with an aqueous solution of analkali metal bisulfite to produce 3(a) ,20-dihydroxy-ll-keto-IZM)-bromo-A -pregnene 21- a1.

EDWARD C. KENDALL. GERARD A. FLEISI-IER.

No references cited.

1. COMPOUNDS OF THE GENERAL FORMULA